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2.
Prostate Cancer Prostatic Dis ; 19(4): 398-405, 2016 12.
Article in English | MEDLINE | ID: mdl-27502737

ABSTRACT

BACKGROUND: Androgen receptor signaling remains important in castration-resistant prostate cancer (CRPC) as demonstrated by the efficacy of abiraterone acetate (henceforth abiraterone) in phase III trials. Given that heterogeneous patient responses are observed, we sought to identify clinical factors associated with duration of abiraterone. METHODS: We retrospectively identified patients with CRPC treated with abiraterone in our database. Patient characteristics and types and duration of prostate cancer (PC) therapies were analyzed. These parameters were analyzed with duration of abiraterone in univariate and multivariable analyses. RESULTS: We identified 161 patients who had received abiraterone. All had received primary androgen-deprivation therapy (ADT), 86% prior secondary hormone therapy (SHT) and 33% prior chemotherapy. The median duration of primary ADT was 23 months, duration of SHT (excluding abiraterone) was 17 months and duration of chemotherapy was 8 months. We demonstrated that lower PSA at abiraterone initiation, longer primary ADT duration, no prior ketoconazole, no prior chemotherapy and longer chemotherapy duration were associated with a longer duration on abiraterone in univariate analysis. In multivariable analysis, duration of primary ADT (duration of abiraterone 9 versus 13 months for ⩽12 versus >12 months, P=0.03) and no use of prior chemotherapy (duration of abiraterone 16 versus 7 months for no versus yes prior chemotherapy, P<0.01) were associated with duration of abiraterone. CONCLUSIONS: Several clinical parameters, including type and duration of prior therapy, are predictive of responsiveness to abiraterone. These parameters are logical and correlate with smaller disease burden or less exposure to PC therapies. This information can help physicians counsel patients about the potential durability of efficacy of abiraterone. Identifying predictive biomarkers that inform patient selection for therapy is critical to optimizing treatment outcomes.


Subject(s)
Abiraterone Acetate/therapeutic use , Antineoplastic Agents/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Aged , Humans , Male , Middle Aged , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/metabolism , Receptors, Androgen/metabolism , Retrospective Studies , Treatment Outcome
3.
Ann Oncol ; 26(4): 812-817, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25600565

ABSTRACT

BACKGROUND: Programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) pathway negatively regulates T-cell-mediated responses. The prognostic impact of PD-L1 expression needs to be defined in urothelial carcinoma (UC). PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tumor samples from 160 patients with UC were retrieved. PD-L1 expression was evaluated by immunohistochemistry using a mouse monoclonal anti-PD-L1 antibody (405.9A11). PD-L1 positivity on tumor cell membrane was defined as ≥5% of tumor cell membrane staining. The extent of tumor-infiltrating mononuclear cells (TIMCs) as well as PD-L1 expression on TIMCs was scored from 0 to 4. A score of 2, 3, or 4 was considered PD-L1-positive. Clinico-pathological variables were documented. The Cox regression model was used to assess the association of PD-L1 expression with overall survival (OS) in patients who developed metastases. RESULTS: TIMCs were present in 143 of the 160 patient samples. Out of 160 samples, 32 (20%) had positive PD-L1 expression in tumor cell membrane. Out of 143 samples with TIMCs, 58 (40%) had positive PD-L1 expression in TIMCs. Smoking history, prior BCG use and chromosome 9 loss did not correlate with PD-L1 expression in either tumor cell membrane or TIMCs. PD-L1 positivity was not different between non-invasive or invasive UC. In patients who developed metastases (M1) and were treated with systemic therapy (n = 100), PD-L1 positivity on tumor cell membrane was seen in 14% of patients and did not correlate with OS (P = 0.45). Out of 89 M1 patients who had evaluable PD-L1 on TIMCs, PD-L1 expression was seen in 33% of patients and was significantly associated with longer OS on multivariate analysis (P = 0.0007). CONCLUSION: PD-L1 is widely expressed in tumor cell membrane and TIMCs in UC. PD-L1 in tumor cells was not predictive of OS. However, positive PD-L1 expression in TIMCs was significantly associated with longer survival in those patients who developed metastases.


Subject(s)
B7-H1 Antigen/metabolism , Biomarkers, Tumor/metabolism , Carcinoma, Transitional Cell/mortality , Lymphocytes, Tumor-Infiltrating/metabolism , Urologic Neoplasms/mortality , Animals , Carcinoma, Transitional Cell/metabolism , Carcinoma, Transitional Cell/secondary , Follow-Up Studies , Humans , Immunoenzyme Techniques , Lymphocytes, Tumor-Infiltrating/pathology , Mice , Prognosis , Survival Rate , Urologic Neoplasms/metabolism , Urologic Neoplasms/pathology
4.
Prostate Cancer Prostatic Dis ; 17(4): 325-31, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25091040

ABSTRACT

BACKGROUND: Understanding the mechanisms driving disease progression is fundamental to identifying new therapeutic targets for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Owing to the prevalence of bone metastases in mCRPC, obtaining sufficient tumor tissue for analysis has historically been a challenge. In this exploratory analysis, we evaluated imaging, procedural and clinical variables associated with tumor yield on image-guided bone biopsy in men with mCRPC. METHODS: Clinical data were collected prospectively from men with mCRPC enrolled on a phase II trial with serial metastasis biopsies performed according to standard clinical protocol. Imaging was retrospectively reviewed. We evaluated the percent positive biopsy cores (PPC), calculated as the number of positive cores divided by the total number of cores collected per biopsy. RESULTS: Twenty-nine men had 39 bone biopsies. Seventy-seven percent of bone biopsies had at least one positive biopsy core. We determined that lesion size and distance from the skin to the lesion edge correlated with tumor yield on biopsy (median PPC 75% versus 42% for lesions >8.8 cm(3) versus ⩽ 8.8 cm(3), respectively, P=0.05; median PPC 33% versus 71% for distance ⩾ 6.1 versus <6.1 cm, respectively, P = 0.02). There was a trend towards increased tumor yield in patients with increased uptake on radionuclide bone scan, higher calcium levels and shorter duration of osteoclast-targeting therapy, although this was not statistically significant. Ten men had 14 soft tissue biopsies. All soft tissue biopsies had at least one positive biopsy core. CONCLUSIONS: This exploratory analysis suggests that there are imaging, procedural and clinical variables that have an impact on image-guided bone biopsy yield. In order to maximize harvest of prostate cancer tissue, we have incorporated a prospective analysis of the metrics described here as part of a multi-institutional project aiming to use the molecular characterization of mCRPC tumors to direct individual therapy.


Subject(s)
Biopsy/methods , Bone Neoplasms/diagnostic imaging , Bone Neoplasms/secondary , Prostatic Neoplasms, Castration-Resistant/pathology , Radiography, Interventional/methods , Aged , Androgen Antagonists/therapeutic use , Androstenes/administration & dosage , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azasteroids/administration & dosage , Drug Resistance, Neoplasm , Dutasteride , Humans , Male , Middle Aged , Prostatic Neoplasms, Castration-Resistant/diagnostic imaging , Radionuclide Imaging , Radiopharmaceuticals , Surgery, Computer-Assisted/methods , Technetium Tc 99m Medronate
5.
Prostate Cancer Prostatic Dis ; 16(3): 266-70, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23712318

ABSTRACT

BACKGROUND: Intermediate end points are desirable to expedite the integration of neoadjuvant systemic therapy into the treatment strategy for high-risk localized prostate cancer. Endorectal magnetic resonance imaging at 1.5 Tesla (1.5T erMRI) response has been utilized as an end point in neoadjuvant trials but has not been correlated with clinical outcomes. METHODS: Data were pooled from two trials exploring neoadjuvant chemotherapy in high-risk localized prostate cancer. Trial 1 explored docetaxel for 6 months and Trial 2 explored docetaxel plus bevacizumab for 4.5 months, both before radical prostatectomy. erMRI was done at baseline and end of chemotherapy. 1.5T erMRI response, based upon T2W sequences, was recorded. Multivariable Cox regression was undertaken to evaluate the association between clinical parameters and biochemical recurrence. RESULTS: There were 53 evaluable patients in the combined analysis: 20 (33%) achieved a PSA response, 16 (27%) achieved an erMRI partial response and 24 (40%) achieved an erMRI minor response. Median follow-up was 4.2 years, and 33 of 53 evaluable (62%) patients developed biochemical recurrence. On multivariable analysis, PSA response did not correlate with biochemical recurrence (hazard ratio=0.58, 95% confidence interval (CI) 0.25-1.33) and paradoxically erMRI response was associated with a significantly shorter time to biochemical recurrence (hazard ratio=2.47, 95% CI 1.00-6.13). CONCLUSIONS: Response by 1.5T erMRI does not correlate with a decreased likelihood of biochemical recurrence in patients with high-risk localized prostate cancer treated with neoadjuvant docetaxel and may be associated with inferior outcomes. These data do not support the use of 1.5T erMRI response as a primary end point in neoadjuvant chemotherapy trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Bevacizumab , Chemotherapy, Adjuvant , Clinical Trials, Phase II as Topic , Docetaxel , Humans , Kallikreins/blood , Magnetic Resonance Imaging/methods , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/surgery , Prospective Studies , Prostate-Specific Antigen/blood , Prostatectomy/methods , Prostatic Neoplasms/blood , Prostatic Neoplasms/surgery , Taxoids/administration & dosage , Treatment Outcome
6.
J Urol ; 172(1): 331-7, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15201806

ABSTRACT

PURPOSE: Various strategies have recently emerged to improve the diagnostic prediction of prostate cancer (CaP). One such strategy includes the mass profiling of serum protein fractions selectively adsorbed onto chemically modified probes. In the current study we further validated this approach, while offering a more versatile, less expensive and yet equally predictive alternative to existing technologies. MATERIALS AND METHODS: A solid core lipophilic C-18 resin was used to extract and enrich the low molecular weight protein fraction from patient serum for further analysis by mass spectrometry. Mass spectra generated from a 48 patient training set were data mined using multivariate analysis to identify diagnostically significant protein peaks. These peaks were then used to test a blinded study set comprising 168 patients with common statistical algorithms and commercially available software packages. RESULTS: A total of 36 peaks generated from the training set were used to test the combined set of 168 serum samples obtained from 98 healthy individuals and 70 patients with CaP. We report a sensitivity of 94.1% and a specificity of 99.0% with 1 false-positive, 4 false-negative and 5 nondiagnosed cases. CONCLUSIONS: Our results further indicate that mass profiling of serological proteins provides a means for the accurate detection of CaP. In addition, our approach was found to be superior to chip based protocols, generating rich, sharp, highly reproducible spectra attainable in a high throughput manner and at minimal cost. This technique is also scaleable for subsequent protein characterization using multidimensional protein identification technologies. Finally, analyses of mass spectra with commercially available statistical applications was found to be highly effective in generating highly discriminatory m/z values for CaP diagnosis.


Subject(s)
Biomarkers, Tumor/analysis , Blood Proteins/analysis , Prostatic Neoplasms/diagnosis , Proteome/analysis , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Humans , Image Processing, Computer-Assisted , Male , Middle Aged , Multivariate Analysis , Protein Array Analysis , Serologic Tests
7.
Semin Oncol ; 28(4 Suppl 15): 32-9, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11685726

ABSTRACT

Over the past 10 years, men with prostate cancer have received earlier diagnoses and are undergoing prostatectomy and/or radiation therapy with curative intent; however, many men have increasing prostate-specific antigen (PSA) levels without evidence of local progression or metastatic disease during the first 2 years after definitive local therapy. Optimal treatment of men with PSA-only recurrent prostate cancer has not been established. This ongoing phase II trial is evaluating docetaxel (70 mg/m(2) administered intravenously over 1 hour on day 2 every 21 days for four cycles) and estramustine (10 mg/kg/d orally on days 1 to 5 every 21 days for four cycles) followed by bicalutamide and goserelin acetate in men with increasing PSA levels after prostatectomy and/or radiation therapy. Patients received pretreatment with dexamethasone, and after the third patient enrolled, patients received warfarin for prophylaxis against thrombosis. Colony-stimulating factor support was allowed. In preliminary results, 11 of 15 patients completed protocol chemotherapy; 12 of 15 patients achieved complete response (ie, normalization of PSA) after four cycles of chemotherapy. In addition, testosterone levels were reduced to the castrate range in all patients after chemotherapy. The regimen was generally well tolerated, and toxicities were mostly hematologic, with grade (3/4) neutropenia reported in approximately half of patients. Preliminary results of this phase II trial are encouraging, and enrollment is ongoing.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Paclitaxel/analogs & derivatives , Prostate-Specific Antigen/blood , Prostatic Neoplasms/drug therapy , Taxoids , Adenocarcinoma/blood , Aged , Docetaxel , Estramustine/administration & dosage , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/blood , Paclitaxel/administration & dosage , Prostatic Neoplasms/blood
9.
Am J Pathol ; 159(1): 79-92, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11438457

ABSTRACT

An antibody, GC-17, thoroughly characterized for its specificity for estrogen receptor-beta (ER-beta), was used to immunolocalize the receptor in histologically normal prostate, prostatic intraepithelial neoplasia, primary carcinomas, and in metastases to lymph nodes and bone. Comparisons were made between ER-beta, estrogen receptor-alpha (ER-alpha), and androgen receptor (AR) immunostaining in these tissues. Concurrently, transcript expression of the three steroid hormone receptors was studied by reverse transcriptase-polymerase chain reaction analysis on laser capture-microdissected samples of normal prostatic acini, dysplasias, and carcinomas. In Western blot analyses, GC-17 selectively identified a 63-kd protein expressed in normal and malignant prostatic epithelial cells as well as in normal testicular and prostatic tissues. This protein likely represents a posttranslationally modified form of the long-form ER-beta, which has a predicted size of 59 kd based on polypeptide length. In normal prostate, ER-beta immunostaining was predominately localized in the nuclei of basal cells and to a lesser extent stromal cells. ER-alpha staining was only present in stromal cell nuclei. AR immunostaining was variable in basal cells but strongly expressed in nuclei of secretory and stromal cells. Overall, prostatic carcinogenesis was characterized by a loss of ER-beta expression at the protein and transcript levels in high-grade dysplasias, its reappearance in grade 3 cancers, and its diminution/absence in grade 4/5 neoplasms. In contrast, AR was strongly expressed in all grades of dysplasia and carcinoma. Because ER-beta is thought to function as an inhibitor of prostatic growth, androgen action, presumably mediated by functional AR and unopposed by the beta receptor, may have provided a strong stimulus for aberrant cell growth. With the exception of a small subset of dysplasias in the central zone and a few carcinomas, ER-alpha-stained cells were not found in these lesions. The majority of bone and lymph node metastases contained cells that were immunostained for ER-beta. Expression of ER-beta in metastases may have been influenced by the local microenvironment in these tissues. In contrast, ER-alpha-stained cells were absent in bone metastases and rare in lymph nodes metastases. Irrespective of the site, AR-positive cells were found in all metastases. Based on our recent finding of anti-estrogen/ER-beta-mediated growth inhibition of prostate cancer cells in vitro, the presence of ER-beta in metastatic cells may have important implications for the treatment of late-stage disease.


Subject(s)
Carcinoma/metabolism , Prostate/metabolism , Prostatic Diseases/metabolism , Prostatic Neoplasms/metabolism , Receptors, Androgen/metabolism , Receptors, Estrogen/metabolism , Aged , Blotting, Western , Carcinoma/pathology , Carcinoma/secondary , Enzyme-Linked Immunosorbent Assay , Estrogen Receptor alpha , Estrogen Receptor beta , Humans , Immunochemistry , Immunohistochemistry , Male , Middle Aged , Prostatic Neoplasms/pathology , Prostatic Neoplasms/secondary , RNA, Messenger/metabolism , Receptors, Estrogen/genetics , Reference Values , Reverse Transcriptase Polymerase Chain Reaction
10.
J Clin Oncol ; 19(9): 2509-16, 2001 May 01.
Article in English | MEDLINE | ID: mdl-11331330

ABSTRACT

PURPOSE: To investigate the combination of docetaxel, estramustine (EM), and low-dose hydrocortisone in men with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Combinations of EM with other antimitotic agents such as docetaxel are synergistic in vitro and show significant clinical activity in patients with HRPC. We studied intravenous administration of docetaxel 70 mg/m(2), oral estramustine, and low-dose daily hydrocortisone in men with HRPC who demonstrated progression after initial hormone therapy. RESULTS: Of the 47 men enrolled onto this multicenter cooperative group study, 46 were assessable for response and/or toxicity. In the 24 patients with measurable disease, there were three complete and nine partial responses for a measurable disease response rate of 50% (12 of 24 patients; 95% confidence interval [CI], 27% to 73%). In the 44 patients in whom pretreatment prostate-specific antigen (PSA) was elevated, 30 (68%) had a 50% or greater decrease, and 25 (57%) had a 75% or greater decrease in PSA. The combined measurable disease and biochemical response rate in all 46 assessable patients was 54% (three complete responses, 22 partial responses, 95% CI, 37% to 71%). The predominant toxicity was neutropenia, with 26% of patients having grade 3 and 30% having grade 4 granulocytopenia; there were no episodes of febrile neutropenia. Other common but mild adverse effects included malaise/fatigue, peripheral edema, and hyperglycemia. The incidence of thromboembolic events during therapy was 9%. With a median follow-up of 17 months, the median survival was 20 months. The median time to disease progression was 8 months for all patients, and 10 months for those with measurable disease. CONCLUSION: This therapy is efficacious and moderately well tolerated in HRPC and should be compared in a phase III trial with mitoxantrone and prednisone.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Paclitaxel/analogs & derivatives , Prostatic Neoplasms/drug therapy , Taxoids , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Docetaxel , Estramustine/administration & dosage , Humans , Hydrocortisone/administration & dosage , Male , Paclitaxel/administration & dosage , Prostatic Neoplasms/mortality , Survival Rate
11.
Semin Oncol ; 26(5 Suppl 17): 39-44, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10604268

ABSTRACT

Combinations of estramustine with other antimitotic agents, such as docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA), are synergistic in vitro and show significant clinical activity in hormone-refractory prostate cancer (HRPC). We have studied intravenous docetaxel 70 mg/m2, oral estramustine, and low-dose daily hydrocortisone in men with HRPC who demonstrated progression after initial hormone therapy. Of the 47 men who were enrolled, 40 are evaluable for response and/or toxicity. One patient (3%) has had a complete response and eight (20%) have had a partial response, yielding a total objective response rate of 23%. Of 39 patients with elevated pretreatment prostate-specific antigen levels who have had at least one posttreatment prostate-specific antigen measurement, 27 (69%) have had > or =50% decreases and 21 (54%) have had > or =75% decreases in prostate-specific antigen levels. Toxicity is modest but manageable. This therapy is efficacious and well tolerated in HRPC and should be compared in phase III trials with other drugs active in HRPC, such as mitoxantrone and hydrocortisone.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms, Hormone-Dependent/drug therapy , Paclitaxel/analogs & derivatives , Prostatic Neoplasms/drug therapy , Taxoids , Adenocarcinoma/blood , Adenocarcinoma/secondary , Aged , Docetaxel , Estramustine/administration & dosage , Humans , Hydrocortisone/administration & dosage , Male , Middle Aged , Neoplasms, Hormone-Dependent/blood , Neoplasms, Hormone-Dependent/pathology , Paclitaxel/administration & dosage , Prostate-Specific Antigen/blood , Prostatic Neoplasms/blood , Prostatic Neoplasms/pathology , Survival Analysis
12.
Cancer Res ; 59(11): 2511-5, 1999 Jun 01.
Article in English | MEDLINE | ID: mdl-10363963

ABSTRACT

The role of androgen receptor (AR) mutations in androgen-independent prostate cancer (PCa) was determined by examining AR transcripts and genes from a large series of bone marrow metastases. Mutations were found in 5 of 16 patients who received combined androgen blockade with the AR antagonist flutamide, and these mutant ARs were strongly stimulated by flutamide. In contrast, the single mutant AR found among 17 patients treated with androgen ablation monotherapy was not flutamide stimulated. Patients with flutamide-stimulated AR mutations responded to subsequent treatment with bicalutamide, an AR antagonist that blocks the mutant ARs. These findings demonstrate that AR mutations occur in response to strong selective pressure from flutamide treatment.


Subject(s)
Androgen Antagonists/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Bone Marrow Neoplasms/genetics , Mutation/genetics , Neoplasms, Hormone-Dependent/genetics , Prostatic Neoplasms/genetics , Receptors, Androgen/genetics , Anilides/therapeutic use , Biopsy , Bone Marrow/pathology , Bone Marrow Neoplasms/secondary , Codon/genetics , DNA Mutational Analysis , Flutamide/therapeutic use , Humans , Male , Neoplasms, Hormone-Dependent/chemistry , Neoplasms, Hormone-Dependent/drug therapy , Neoplasms, Hormone-Dependent/pathology , Nitriles , Prostatic Neoplasms/chemistry , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Reverse Transcriptase Polymerase Chain Reaction , Tosyl Compounds
13.
J Urol ; 159(1): 149-53, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9400459

ABSTRACT

PURPOSE: A pilot study of the antiandrogen bicalutamide at 150 mg. a day for androgen independent prostate cancer was performed. This study was based on the possibility that androgen independent cases might display responses to additional hormonal agents. MATERIALS AND METHODS: The study included 31 androgen independent cases with an increasing prostate specific antigen (PSA) and progressive disease. PSA measurements were used as the primary method of assessing response. However, PSA decline was also correlated with clinical status. RESULTS: Seven patients demonstrated PSA declines of greater than 50% for 2 months or more, for an overall response rate of 22.5%. Responses were observed almost exclusively in patients treated with long-term flutamide as part of a complete androgen blockade regimen (43% response rate) in contrast to patients treated with androgen deprivation without flutamide (6% response rate). Of the 7 PSA responding patients bicalutamide resulted in a significant improvement in performance status and a decrease in analgesic requirement in 4 and 3 remained asymptomatic. Bicalutamide at 150 mg. a day was well tolerated, with the most frequent side effect being mild exacerbation of hot flashes. CONCLUSIONS: Bicalutamide at this dose is modestly effective for some patients with androgen independent prostate cancer, particularly for those previously treated with long-term flutamide. This study indicates that previous antiandrogen therapy alters the response to subsequent hormonal agents.


Subject(s)
Androgen Antagonists/therapeutic use , Anilides/therapeutic use , Antineoplastic Agents/therapeutic use , Prostatic Neoplasms/drug therapy , Aged , Aged, 80 and over , Antineoplastic Agents, Hormonal/therapeutic use , Flutamide/therapeutic use , Humans , Male , Middle Aged , Nitriles , Pilot Projects , Prostate-Specific Antigen/blood , Prostatic Neoplasms/blood , Tosyl Compounds
14.
Clin Cancer Res ; 3(8): 1383-8, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9815822

ABSTRACT

Mutations in the androgen receptor (AR), that alter steroid hormone specificity have been identified in a series of androgen-independent prostate cancers. To address the functional properties of these mutant ARs that may have contributed to their selection in vivo, responses to a series of steroid hormones and antiandrogens were assessed. CV-1 cells were cotransfected with wild-type or mutant ARs and a luciferase reporter plasmid regulated by an androgen-responsive element. Dose-response curves were analyzed for 5alpha-dihydrotestosterone, the most active androgen in normal prostate, and androstenedione, a major androgen derived from the adrenals. Although the mutant ARs responded to both of these steroids, the responses were equivalent to or less than the wild-type AR. In contrast, responses to flutamide, a competitive antagonist of the wild-type AR, were markedly increased by three of the mutations. Similar responses were observed with a second antiandrogen, nilutamide. Bicalutamide, another antiandrogen related to flutamide, remained an antagonist for these mutant ARs. Finally, flutamide was observed to be a weak partial agonist of the wild-type AR in this system. These results indicate that flutamide used in conjunction with androgen ablation therapy for prostate cancer may select for tumor cells with flutamide-inducible ARs.


Subject(s)
Androgen Antagonists/pharmacology , Androgens/pharmacology , Imidazolidines , Point Mutation , Prostatic Neoplasms/genetics , Receptors, Androgen/genetics , Amino Acid Substitution , Androstenedione/pharmacology , Animals , Cell Line , Dihydrotestosterone/pharmacology , Estradiol/pharmacology , Flutamide/analogs & derivatives , Flutamide/pharmacology , Genes, Reporter , Imidazoles/pharmacology , Luciferases/genetics , Male , Progesterone/pharmacology , Prostatic Neoplasms/metabolism , Receptors, Androgen/biosynthesis , Receptors, Androgen/physiology , Recombinant Fusion Proteins/biosynthesis , Transfection , beta-Galactosidase/genetics
15.
Immunology ; 87(3): 402-7, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8778025

ABSTRACT

Several lines of evidence indicate that a subset of murine intestinal intraepithelial lymphocytes (iIEL), particularly those which express the CD8 alpha alpha homodimer, mature extrathymically. This study confirms that a small fraction of adult human iIEL also express the CD8 alpha alpha homodimer and demonstrates that most of these cells in the small intestine are T cells using the alpha beta T-cell receptor (TCR). Whether these cells or other subsets of adult human iIEL mature extrathymically in the intestine was assessed by measuring the expression of terminal deoxynucleotidyltransferase (TdT), an enzyme expressed exclusively by immature lymphocytes. Very low levels of TdT message could be detected by polymerase chain reaction (PCR) amplification in some iIEL samples. The level of TdT expression was assayed by competitive PCR amplification and compared with thymocytes and peripheral blood lymphocytes. These measurements indicated that the number of immature T cells expressing TdT in the intestinal epithelium was less than one cell per 10(7) lymphocytes. This demonstrates that there are few if any TdT expressing immature T cells in the adult human intestinal mucosa and indicates, therefore, that T-cell development in the intestinal mucosa does not contribute significantly to the T-cell repertoire of the adult human intestine.


Subject(s)
DNA Nucleotidylexotransferase/metabolism , Intestinal Mucosa/immunology , T-Lymphocytes/physiology , Adult , Cell Cycle , DNA Nucleotidylexotransferase/analysis , DNA Primers/genetics , Fluorescent Antibody Technique , Humans , Immunity, Cellular , Intestinal Mucosa/enzymology , Molecular Sequence Data , Polymerase Chain Reaction , T-Lymphocytes/enzymology
16.
N Engl J Med ; 332(21): 1393-8, 1995 May 25.
Article in English | MEDLINE | ID: mdl-7723794

ABSTRACT

BACKGROUND: Metastatic prostate cancer is a leading cause of cancer-related death in men. The rate of response to androgen ablation is high, but most patients relapse as a result of the outgrowth of androgen-independent tumor cells. The androgen receptor, which binds testosterone and stimulates the transcription of androgen-responsive genes, regulates the growth of prostate cells. We analyzed the androgen-receptor genes from samples of metastatic androgen-independent prostate cancers to determine whether mutations in the gene have a role in androgen independence. METHODS: Complementary DNA was synthesized from metastatic prostate cancers in 10 patients with androgen-independent prostate cancer, and the expression of the androgen-receptor gene was estimated by amplification with the polymerase chain reaction. Exons B through H of the gene were cloned, and mutations were identified by DNA sequencing. The functional effects of the mutations were assessed in cells transfected with mutant genes. RESULTS: All androgen-independent tumors expressed high levels of androgen-receptor gene transcripts, relative to the levels expressed by an androgen-independent prostate-cancer cell line (LNCaP). Point mutations in the androgen-receptor gene were identified in metastatic cells from 5 of the 10 patients examined. One mutation was in the same codon as the mutation found previously in the androgen-independent prostate-cancer cell line. The mutations were not detected in the primary tumors from of the two patients. Functional studies of two of the mutant androgen receptors demonstrated that they could be activated by progesterone and estrogen. CONCLUSIONS: Most metastatic androgen-independent prostate cancers express high levels of androgen-receptor gene transcripts. Mutations in androgen-receptor genes are not uncommon and may provide a selective growth advantage after androgen ablation.


Subject(s)
Point Mutation , Prostatic Neoplasms/genetics , Receptors, Androgen/genetics , Base Sequence , Bone Marrow Diseases/genetics , DNA, Complementary/biosynthesis , DNA, Neoplasm/biosynthesis , Estradiol/metabolism , Humans , Male , Molecular Sequence Data , Neoplasm Metastasis , Prostatic Neoplasms/metabolism , Testosterone/metabolism , Transcription, Genetic , Tumor Cells, Cultured
17.
Arch Intern Med ; 148(5): 1064, 1988 May.
Article in English | MEDLINE | ID: mdl-3365077

ABSTRACT

A patient with persistent diarrhea was found to have biopsy-proved colitis with large numbers of the protozoan Blastocystis hominis present in stool. Extensive evaluation failed to reveal any other potential etiologic agent of acute colitis. Following treatment with a course of metronidazole, the patient became asymptomatic, B hominis was no longer present in stool, and results of a repeated biopsy were normal. These observations are consistent with the role of B hominis as a gastrointestinal pathogen.


Subject(s)
Colitis/parasitology , Intestinal Diseases, Parasitic/parasitology , Protozoan Infections , Aged , Humans , Male
18.
Am J Clin Pathol ; 85(1): 32-6, 1986 Jan.
Article in English | MEDLINE | ID: mdl-3940418

ABSTRACT

Vitamin B12 concentration was determined by radioassay in 179 healthy volunteers between the ages of 20 and 93 years in order to determine whether vitamin B12 levels decline with advancing age. The authors found no statistically significant decline in vitamin B12 levels in older individuals, nor a difference between males and females. A review of previous reports identifies potential reasons for controversy regarding the normal concentration of vitamin B12 in the elderly.


Subject(s)
Aging , Vitamin B 12/blood , Adult , Aged , Female , Humans , Male , Middle Aged , Radioimmunoassay , Reference Values
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